Cellular transplantation has recently generated enthusiasm for treating a number of human diseases characterized by hormone or protein deficiencies, such as diabetes, Parkinson's disease, Huntington's disease, liver disease and others. However, a number of technical and logistical challenges have prevented cellular transplantation from working effectively. In particular, transplanted cells must be protected from immune attack by the transplant recipient. This often requires potent immunosuppressive agents having considerable toxicity that can expose the patient to a wide variety of serious side effects. While immunosuppressive agents increase the chance that the host will accept the cell therapy treatment, it has been well documented that immunosuppressive drugs can cause deleterious effects to the host. In particular, immunosuppressive agents lower a subject's resistance to infection, make infections harder to treat, and increase the chance of uncontrolled bleeding. The drugs may also be harmful to the transplanted cells.
An alternative approach is to enclose the transplanted cells within a semi-permeable membrane. In theory, the semi-permeable membrane is designed to protect cells from immune attack while allowing for both the influx of molecules important for cell function and survival and the efflux of the desired cellular product, for example insulin. This immunoisolation approach has two major potentials: i) cell transplantation without the need for immunosuppressive drugs and their accompanying side effects, and ii) use of cells from a variety of sources such as autografts (host stem-cell derived), allografts (either primary cells or stem-cell derived), xenografts (porcine cells or others), or genetically engineered cells.
Macro-immunoisolation systems including intravascular and diffusive devices (e.g., hollow fibers, tubular membranes, flat sandwich pouches, islet sheets, and islet patches) have been tested in diabetic rodents and dogs, and results indicate that many of these systems can function for periods of time. However, these designs have limited application, because implantation is highly invasive surgically, device failure is common, and the side effects of device failure are high. For example, a single breach in macro diffusion devices can cause massive islets death and system failure, and if the breach is sudden, a lethal dose of insulin can be released from the islets, causing death of the host.
Micro-immunoisolation systems, although they overcome many of the problems associated with macro systems, have their own drawbacks. Certain microimmunoisolation systems have been tested in large animal models, but many of those experiments were performed on spontaneous diabetic subjects or utilized immunosuppressive agents. Sun et al. “Normalization of diabetes in spontaneously diabetic cynomolgus monkeys by xenografts of microencapsulated porcine islets without immunosuppressant” J. Clin. Invest. 98:1417-22 (1996); Lanza et al. “Transplantation of islets using microencapsulation: studies in diabetic rodents and dogs” J. Mol. Med. 77(1):206-10 (1999); R. Calafiore “Transplantation of minimal volume microcapsules in diabetic high mammalians” Ann NY Acad. Sci. 875:219-32 (1999); Hering et al. “Long term (>100 days) diabetes reversal in immunosuppressed nonhuman primate recipients of porcine islet xenographs” American J. Transplantation 4:160-61 (2004); and Soon-Shiong et al. “Insulin independence in a Type 1 diabetic patient after encapsulated islet transplantation” Lancet 343:950-951 (1994). Moreover, many of these experiments could not be reproduced to acceptable scientific standards. The lack of experimental control and consistency of those experiments has complicated scientific interpretation and limited their applicability.
Prior micro-immunoisolation systems have involved the transplantation of encapsulated cells directly into the body cavity of the subject, for example by hypodermic injection or by creating a surgical opening in the body cavity and introducing the encapsulated cells into the body cavity through the opening. Once inside the body cavity, the encapsulated cells could then migrate or diffuse in the body cavity, and may attach to undesirable locations, for example the outer wall of the liver or kidney, which could disrupt the function of those organ, leading to other medical concerns. Micro-immunoisolation systems also suffer from the effects of gravitational sedimentation, which can lead to undesirable system migration and clumping of encapsulated cells within the body, which can cause a number of undesirable side effects and prevent effective functioning of the implant.
Thus, the promise of immunoprotection of living cells to treat hormone-deficient diseases has not been realized. Accordingly, what is needed in the art is a reproducible and effective cell therapy treatment that can be used in large mammals including humans without the use of immunosuppressive drugs.